Theoretical study of electronic properties of few variants

Advances in Physics Theories and Applications www.iiste.org

ISSN 2224-719X (Paper) ISSN 2225-0638 (Online)

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Theoretical Study of Electronic Properties of few Variants of Gingerol, a Group of Biologically Active Compounds

Nabajyoti Baildya and Asoke Prasun Chattopadhyay* Department of Chemistry

University of Kalyani, Kalyani 741235 India [email protected]

Abstract This work presents the first theoretical studies of gingerol, an important biological extract from ginger

oil, and its variants viz. 6-gingerol, 6-paradol, 6-shogaol, 8-gingerol, 10-gingerol and gingerone. Standard DFT calculations reveal some effect on side chains on properties such as optimized structures, electronic states, energy gaps, electronic potential, hardness, electrophilicity and dipole moment. The harmonic vibration frequencies and 1H-NMR data for the molecules have also been calculated. Finally, docking studies of gingerol and its variants with the human protein leukotriene A-4 hydrolase (PDB ID: 1HS6) show stable binding of the molecules with the latter. Keywords: B3LYP, DFT, Optimization, electronic properties, vibration frequency, 1H-NMR, docking. Introduction

Chemically, gingerol is a relative of capsaicin and piperine, the compounds which give chilli peppers and black pepper their respective spiciness[1]. It is normally found as a pungent yellow oil, but also can form a low-melting crystalline solid. Gingerol seems to be effective in an animal model of rheumatoid arthritis[2]. It may reduce nausea caused by motion sickness or pregnancy[3] and may also relieve migraine[4]. 6-Gingerol has been used to induce a hypothermic state in rats[5]. Gingerol has been investigated for its effect on cancerous tumors in the bowel,[6] in breast tissue,[7] ovaries,[8] pancreas[9] etc., with beneficial results. The reason behind the choosing these six variants are due to their anti-emetic properties, action on central nervous system, antitussive activity, action on endocrine system etc[10].

Much work has been done on gingerol, but we have not found any theoretical calculation so far. In the present work, we calculate some physical properties of the gingerol variants along with their IR stretching frequencies, and also their proton NMR spectra. We have also attempted docking of these variants with human protein leukotriene A-4 hydrolase. Among the molecules studied here, only binding of 6-gingerol with this protein is reported in the literature. We predict the binding pattern of other variants with the same protein. We also show possible modes of binding and also the lowest energy of the binding ligands with protein.

Computational details:

All computations were carried out using the density functional theory (DFT) methods implemented in the Gaussian 09 suite of programs. Geometry optimization and molecular properties of the compounds, esp. vibration frequencies, dipole moment etc., were computed at DFT level using the standard 6-31g(d) basis sets[11-13] with B3LYP functional[14-16]. NMR shielding constants were calculated in the GIAO method [17,18] with the same basis and functional, at the optimized geometry. Docking of the variants of gingerol with the protein was performed using Autodock 4.2 software [19] and the docking structure was analyzed by Accelrys Discovery Studio client (version 3.5, free for academic use). ChemUltra3D software was also used in this regard.

Optimized structures of all molecules are shown in Fig. 1. Some relevant electronic properties such as electronic potential (IP), electron affinity (EA), chemical potential (μ), electronegativity (χ), hardness (η), softness (S) and electrophilicity index (ω) were calculated at the optimized geometries of the molecules. These are displayed in Table 1. The ionization potential is calculated as the energy difference between cation and the neutral molecule i.e. IP = Ecation - En, and also by Koopmans approximation as IP = - ɛHOMO[20]. The first method is called ∆SCF. These methods have also been termed as Energy-vertical and Orbital-vertical respectively [21].Similarly, the electron affinity is calculated as the difference between the neutral molecule and the anion as EA = En - Eanion and also by Koopmans method as EA = - ɛLUMO[22].

The chemical potential, which measures the escaping tendency of an electronic cloud, and equals the slope of the energy versus the number of electrons (N) curve at external potential v(r)[23].

μ = [ ]v(r) .....................................(1)

Again chemical potential is the negative of electronegativity and thus given by, μ = −χ = − ................................(2)

Again hardness is defined as the corresponding second derivative and given by,

η = [ ]v(r) = [ ] v(r).................(3)

Finite difference approximation to chemical hardness gives:



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η = ............................................(4)

Or difference of energy gaps give the hardness i.e. η = ɛLUMO - ɛHOMO ..............................(5) Softness is given by the reciprocal of hardness S = 1/ η ................................................(6) The electrophilic index is a measure of energy lowering due to maximal electron flow between donor and acceptor. Electrophilic index (ω) is defined as:

ω = ..................................................(7)

Results and discussion

The energy of optimized structure of molecules under study calculated by DFT-B3LYP levels with the 6-31G(d) basis sets are listed in Table 1 with their respective B3LYP energies.

Other physical properties are displayed in Table 2. These properties for each variant are computed by two different ways: The first one being the ∆SCF and the second is the Koopman’s method (“Koop” in Table 2). All parameters in Table 2, and most in Table 1 are in atomic units. Only the dipole moment is in Debye units, in Table 1. Apparently, there does not seem any correlation between the values presented and the structures of the molecules. However, in two cases we have found some relation. Electron affinity values seem to be negatively correlated with sizes of the molecules, calculated as the largest end-to-end distance between atoms (not considering hydrogens), as follows.

EA = 0.28977 – 0.000188 x size The correlation coefficient was 0.845. The data are plotted in Fig. 2. Similarly, electronegativity values are also negatively correlated with sizes of molecules, but in a more complex manner, as given below. χ = 0.26453 + 1.04103 x exp (- size/15.48813) Here also the correlation is about 0.82. The data are shown in Fig. 3. These relations must be explored further.

IR vibration frequencies:

The theoretical IR spectra, calculated from the vibration frequencies at the optimized geometries, of all the gingerol variants are given in Fig. 4. The C-H stretching vibration for aromatic molecules falls in the region 2900-3250 cm-1 which is characteristic and used for ready identification, particularly the region 3250-3100 cm-1 for asymmetric stretching and 3100-2900 cm-1 for symmetric stretching modes of vibrations of aromatic C-H bonds [24]. Again for sp3 carbon, the C-H stretching frequency is expected in the region 2850-3000 cm-1. For the free phenolic O-H, the stretching vibration is 3580-3650 cm-1. For saturated ketones, the IR stretching vibration appears in the region 1710-1720 cm-1. See, for example [25]. Some major bands from our calculations are reported in Table 3 below.

The IR bands of the studied molecules as discussed above seem satisfactory. Theoretical IR spectra of the molecules are given in Fig 4. In these figures, some vibrational spectral lines other than the major ones given above, are also seen. These may arise due to the various vibrational modes of C-H bonds like scissoring, rocking, waging and their interactions. Bending vibrations are also responsible for the IR peaks and bands in the low frequency region.

1H NMR spectral data

The 1H-NMR spectra of all the gingerol variants are given in Fig. 5. We must note that in all the variants of gingerol, mainly three types of protons are present. One is aromatic, another is etherial and the other is 20-aliphatic type. Only for 6-shogaol two vinylic protons are present. Now for the aromatic protons the peak is expected at 6.5-8 ppm, for 20-aliphatic groups the peak may appear at or near 1.3 ppm, for the etherial group the peak may be seen at 3.2-4 ppm and for the conjugated vinylic group, it will be in the region 5.5-7.5 ppm.

Our theoretical nmr data are tabulated below (Table 4) for all the gingerol variants. These are in good agreement with the expected values as per discussion above, and also with key results of other workers [26,27].

The slight deviation from actual data of 1H-NMR spectra are due to the presence of various groups like carbonyl, alcoholic etc. i.e. due to shielding and deshielding arises for these groups.

Docking information

Finally, we investigated the binding pattern of these molecules with the human protein leukotriene-A-4-hydrolase (LTA4H). Among these six variants, the binding of only 6-gingerol with this protein has been reported. However, we studied the binding with all other variants of gingerol as well. The molecules were docked into the cavities inside the protein cavity in various patterns. Details are given in Supplementary Information. Only the strongest (i.e. energetically most favourable) binding mode is reported here.



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From our theoretical data, it is seen that 6-gingerol binds with the protein in the strongest manner vis-a-vis the other variants. Most stable binding modes of all gingerol variants with this protein is shown, in 2D fashion, in Fig. 6. Energetics of binding is presented in Table 5. Conclusion

Density functional (DFT) study has been carried out on gingerol and its variants. The calculated electronic properties such as ionization potential, electron affinity, electronegativity, hardness, softness, electrophilic index were calculated by two different ways viz. ∆SCF and Koopmans methods. Electron affinity and electronegativity are negatively correlated with size of the molecules.Theoretical vibrational (IR) spectra of the molecules have also been calculated, which give results near expected regions. Theoretical proton NMR spectra of the molecules were also computed, again giving results close to expectations. Finally, docking of all the molecules with a protein leukotriene-A-4-hydrolase was studied, and most stable binding modes obtained.

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0-340-83149-9, 426. 2. Funk, J.L., Frye, J.B., Oyarzo, J.N. & Timmermann, B.N. (2009), "Comparative Effects of Two Gingerol-

Containing Zingiber Officinale Extracts on Experimental Rheumatoid Arthritis", Journal of Natural Products 72, 403–407.

3. Ernst, E. & Pittler, M.H. (2000), "Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials ", British journal of anaesthesia 84, 367–371.

4. Mustafa, T. & Srivastava, K. (1990), "Ginger (zingeber officinale) in migraine headache", Journal of Ethnopharmacology 29, 267–273.

5. Ueki, S., Miyoshi, M., Shido, O., Hasegawa, J. & Watanabe, T. (2008), "Systemic administration of [6]-gingerol, a pungent constituent of ginger, induces hypothermia in rats via an inhibitory effect on metabolic rate ", European Journal of Pharmacology 584, 87–92.

6. Jeong, C.H., Bode, A.M., Pugliese, A., Cho. Y.Y., Kim, H.G., Shim, J.H., Jeon, Y.J., Li, H. et al. (2009), "[6]-gingerol Suppresses Colon Cancer Growth by Targeting Leukotriene A4 Hydrolase",Cancer Research 69, 5584–5591.

7. Lee, H., Seo, E., Kang, N. & Kim, W. (2008), "[6]-gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells", The Journal of Nutritional Biochemistry 19, 313–9.

8. Rhode, J., Fogoros, S., Zick, S., Wahl, H., Griffith, K.A., Huang, J. & Liu, J.R. (2007), "Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells", BMC Complementary and Alternative Medicin 7,44.

9. Park, Y.J., Wen, J., Bang, S., Park, S.W. & Song, S.Y. (2006), "[6]-Gingerol Induces Cell Cycle Arrest and Cell Death of Mutant p53-expressing Pancreatic Cancer Cells", Yonsei Medical Journal 47, 688–697.

10. Singh, A., Duggal, S., Singh, J. & Katekhaye, S. (2010), "hermographic detection of gingering in horses", IJCP, Vol. 1, Issue 02, 1-5.

11. Ditchfield, R., Hehre, W.J. & Pople, J.A. (1971), "Self-Consistent Molecular-Orbital Methods. IX. An Extended Gaussian Type Basis for Molecular-Orbital Studies of Organic Molecules", J. Chem. Phys. 54, 724-728.

12. Ditchfield, R., Hehre. W.J. & Pople, J.A. (1972), "Self-Consistent Molecular-Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular-Orbital Studies of Organic Molecules", J. Chem. Phys. 56, 2257-2261.

13. Francl, M.M., Pietro, W.J., Hehre, W.J., Binkley, J.S., Gordon, M.S., deFries, D.J. & Pople, J.A. (1982), "Self-Consistent Molecular-Orbital Methods. XXIII. A Polarization-Type Basis Set for second-row elements", J. Chem. Phys. 77, 3654-3665.

14. Becke, A.D. (1988), "Density-functional exchange-energy approximation with current asymptotic behavior", Phys. Rev. A38, 3098-3100.

15. Becke, A.D. (1993), "Density-functional thermochemistry. III. The role of exact exchange", J. Chem. Phys. 98, 5648-5652.

16. Lee, C., Yang, W. & Parr, R.G. (1988), "Development of Colle-Salvetti correlation-energy formula into a functional of the electron density", Phys. Rev. B37, 785-789.

17. Wolinski, K., Hilton, J.F. & Pulay, P. (1990), "Efficient implementation of the Gauge-Independent Atomic Orbital method for NMR chemical shift calculations ", J. Am. Chem. Soc. 112, 8251-8260.

18. Osmilowski, B.O., Kolehmainen, E. & Gawinecki, R. (2001), "", Magn. Reson. Chem. 39, 334-340. 19. Trott, O. & Olson, O.J. (2010), "AutoDock Vina: improving the speed and accuracy of docking with a new

scoring function, efficient optimization and multithreading", J. Comput. Chem. 31, 455-461.



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20. Sadasivam, K. & Kumaresan, R. (2011), "Theoretical investigation on the antioxidant behavior of chrysoeriol and hispidulin flavonoid compounds - A DFT study", Computational and Theoretical Chemistry 963, 227-235.

21. Hasan, N. B. (2013), “Theoretical study of electronic properties of some aromatic rings: B3LYP/DFT calculations”, Adv. Phys. Theories Appl. 24, 83-91

22. Demetrio, D.S.A., Coropceanu, V., Fichou, D. et al. (2007), "", Phil. Trans. R. Soc. A 365, 1435-1452. 23. Chattaraj, P.K., Sarkar, U. & Roy, D.R. (2006), "Electrophilicity Index.", Chem. Rev. 106, 2065-2091. 24. Gümüs, S.T. (2011), "A computational study of substituted diazabenzenes", J. Chem. 35, 803-808. 25. Stuart, B. (2004), "Infrared Spectroscopy. Fundamentals and Applications", John Wiley & Sons. Ch. 4. 26. Halling, M.D., Bell, J.D., Pugmire, R.J., Grant, D.M. & Miller, J.S. (2010), "", J. Phys. Chem. A 114, 6622-

6629. 27. Phalgune, U.D., Vanka, K. & Rajamohan, P.R. (2013), "", Magn. Reson. Chem. 51, 767-774.

6-gingerol 6-paradol

6-shogaol 8-gingerol

10-gingerol zingerone

Fig. 1: Optimized structures of all gingerol variants



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Fig. 2. Correlation between electron affinity and size of the molecules. Fig. 3. Correlation between electronegativity and size of the molecules.

60 80 100 120 140 160

0.262

0.264

0.266

0.268

0.270

0.272

0.274

0.276

0.278

0.280E

lect

ron

affi

nity

(a.

u.)

Size of molecules (a.u.)

60 80 100 120 140 160

0.262

0.264

0.266

0.268

0.270

0.272

0.274

0.276

0.278

0.280

Ele

ctro

neg

ativ

ity (

a.u

.)

Size of molecules (a.u.)



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Fig. 4: The IR spectra of molecules under study, Epsilon ≡ Intensity (Km/mol)



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Fig. 5: 1H-NMR spectra of studied molecules in TMS.



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Fig. 6: Binding of gingerol variants with LTA4H protein



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Table 1: Total energy, electronic states and energy gaps and dipole moments for molecules

Molecule Total Energy (SCF) (a.u.)

Eigenvalues (a.u.) Energy gaps (a.u.) DM (debye)

HOMO LUMO

6-gingerol (1) -964.34414 -0.19452 -0.00972 0.1848 2.8083

6-paradol (2) -889.14119 -0.20005 -0.01093 0.18912 0.4961

6-shogoal (3) -887.90343 -0.19411 -0.04828 0.14583 2.7074

8-gingerol (4) -1042.97136 -0.19412 -0.00966 0.18446 3.0764

10-gingerol (5) -1121.59948 -0.19589 -0.00985 0.18604 3.0085

Zingerone (6) -653.25731 -0.20044 -0.01330 0.18714 0.3694

Table 2: The electronic properties of the molecules

Mol. IP (a.u.) EA (a.u.) χ (a.u.) η (a.u.) S (a.u.) ω (a.u.)

∆SCF Koop ∆SCF Koop ∆SCF Koop ∆SCF Koop ∆SCF Koop ∆SCF Koop

1 0.3473 0.1945 0.1795 0.0097 0.2634 0.1021 0.1678 0.1848 5.9591 5.4112 0.2067 0.0282

2 0.3619 0.2001 0.1783 0.0109 0.2701 0.1055 0.1836 0.1891 5.4454 5.2876 0.1986 0.0294

3 0.3418 0.1941 0.1857 0.0483 0.2638 0.1212 0.1561 0.1458 6.4082 6.8573 0.2229 0.0504

4 0.3445 0.1941 0.1811 0.0097 0.2628 0.1019 0.1635 0.1845 6.1173 5.4213 0.2112 0.0281

5 0.3514 0.1959 0.3087 0.0098 0.3301 0.1029 0.0427 0.1860 23.386 5.3752 1.2738 0.0284

6 0.3735 0.2004 0.1844 0.0133 0.2789 0.1069 0.1892 0.1871 5.2865 5.3436 0.2057 0.0305

Table 3: IR stretching vibration frequencies of the molecules

Molecule Group IR vibration frequencies (cm-1) (range) (our data)

6-GINGEROL C-H, O-H, C=O 2970-3210, 3760, 1798

6-PARADOL C-H, O-H, C=O 3010-3218, 3706, 1805

6-SHOGAOL C-H, O-H, C=O 3012-3228, 3752, 1783

8-GINGEROL C-H, O-H, C=O 2970-3210, 3759, 1798

10-GINGEROL C-H, O-H, C=O 2969-3213, 3705, 1798

ZINGERONE C-H, O-H, C=O 3020-3219, 3705, 1812



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Table 4: 1H-NMR spectral data for the molecules.

Molecule Group NMR data (ppm) (solvent TMS)

6-GINGEROL

Aromatic proton

20-aliphatic proton

Etherial proton

5.6-6

0.7-1.8

3.2-3.4

6-PARADOL

Aromatic proton

20-aliphatic proton

Etherial proton

5.9-6.2

0.7-1.4

3.3-3.6

6-SHOGAOL

Aromatic proton

20-aliphatic proton

Etherial proton

Vinylic proton

5.7-6.2

0.7-1.3

2.7-3.2

6.8

8-GINGEROL

Aromatic proton

20-aliphatic proton

Etherial proton

5.7-6.1

0.7-1.2

3.2-3.4

10-GINGEROL

Aromatic proton

20-aliphatic proton

Etherial proton

5.8-6.3

0.7-1.3

3.2-3.4

ZINGERONE

Aromatic proton

20-aliphatic proton

Etherial proton

5.9-6.2

1.5-2.5 (high due to C=O gr.)

3.3-3.6

Table 5: Binding Energy of different molecules after docking with the protein LTA4H

Molecules Binding energy of the molecules after docking with protein

(kcal/mol)

6-GINGEROL -6.7

6-PARADOL -8.8

6-SHOGAOL -9.1

8-GINGEROL -7.2

10-GINGEROL -8.0

ZINGERONE -6.5

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